The metastatic spread of cancer cells within host tissue is dependent upon the local microenvironment surrounding the primary tumor. Within this microenvironment, cancer cells stimulate surrounding stromal cells to express factors required for remodeling of the host tissue thus allowing for the survival, proliferation and metastasis of the tumor (Liotta & Kohn (2001) Nature 411(6835):375-379). Therefore, an understanding of the molecules mediating tumor-stromal cell interactions is critical for the development of strategies needed to diagnose and treat metastatic cancers. This need is underscored by the fact that many molecules identified as biological markers for metastatic cells are also expressed by host cells under normal physiological conditions (Gabison, et al. (2005) Biochimie 87(3-4):361-368). One particularly good example of such a molecule is the cell surface glycoprotein basigin. Basigin is an integral membrane glycoprotein belonging to the immunoglobulin superfamily (IGSF) and it is expressed on numerous cell types (Gabison, et al. (2005) supra; Yan, et al. (2005) Thromb. Haemost. 93(2):199-204; Muramatsu & Miyauchi (2003) Histol. Histopathol. 18(3):981-987). Originally identified in LX-1 lung carcinoma cells as a secreted factor capable of stimulating the collagenase activity of human fibroblasts, basigin has been identified independently in several different model systems resulting in a long list of acronyms for this molecule including Tumor Collagenase Stimulatory Factor (TCSF) (Biswas (1982) Biochem. Biophys. Res. Commun. 109(3):1026-1034; Biswas (1984) Cancer Lett. 24(2):201-207; Nabeshima, et al. (1991) Arch. Biochem. Biophys. 285(1):90-96), EMMPRIN (Biswas, et al. (1995) Cancer Res. 55(2):434-439), neurothelin (Seulberger, et al. (1992) Neurosci. Lett. 140(1):93-97), OX-47 (Fossum, et al. (1991) Eur. J. Immunol. 21(3):671-679), gp42 (Altruda, et al. (1989) Gene 85(2):445-451), CE9 (Nehme, et al. (1993) J. Cell Biol. 120(3):687-694), 5A11 (Fadool & Linser (1993) Dev. Dyn. 196(4):252-262), HT7 (Seulberger, et al. (1990) EMBO J. 9(7):2151-2158), M6 (Kasinrerk, et al. (1992) J. Immunol. 149(3):847-854), OK blood antigen (Spring, et al. (1997) Eur. J. Immunol. 27(4):891-897), and most recently CD147 ((1996) Tissue Antigens 48(4 Pt 2):352-508). Basigin is the approved HUGO Gene Nomenclature Committee designation for the human gene and will be used to refer to the gene sequence and the expressed proteins herein.
Human basigin has been shown to be expressed as two differentially spliced isoforms encoded by a single gene found on chromosome 19p13.3 (Kaname, et al. (1993) Cytogenet. Cell Genet. 64(3-4):195-197; Guo, et al. (1998) Gene 220(1-2):99-108; Hanna, et al. (2003) BMC Bioche. 4:17(18-20). The molecule is characterized by the presence of two extracellular immunoglobulin-like domains, a single transmembrane domain possessing a charged amino acid and a short cytoplasmic tail containing a basolateral membrane targeting motif (Miyauchi, et al. (1991) J. Biochem. (Tokyo) 110(5):770-774; Deora, et al. (2004) Mol. Biol. Cell 15(9):4148-4165). The more recently identified retina-specific isoform of basigin is distinguished by an additional immunoglobulin-like sequence in the extracellular domain of the protein (Hanna, et al. (2003) supra; Ochrietor, et al. (2003) Invest. Ophthalmol. Vis. Sci. 44(9):4086-4096). According to the current naming system of the National Center for Biotechnology Information, the larger retina-specific isoform has been renamed basigin-1 (GENBANK Accession No. NM—001728.2 and NP—001719.2) and the prototypical isoform, possessing two immunoglobulin domains, has been renamed basigin-2 (GENBANK Accession No. NM—198589.1 and NP—940991.1). Both basigin isoforms are variably glycosylated on asparagine residues, which results in significant alterations in their relative molecular weights depending upon the extent of β1,6-branched polylactosamine incorporation during transit of the protein through the Golgi (Ochrietor, et al. (2003) supra; Tang, et al. (2004) Mol. Biol. Cell 15(9):4043-4050).
Several functions have been described for basigin within both normal and malignant tissues. The best characterized function for basigin is its ability to induce the expression of matrix metalloproteinases (MMPs) in stromal cells. Studies using tumor cell-stromal cell co-culture systems, or the treatment of stromal cells with soluble basigin protein demonstrated that basigin stimulates expression of several MMPs including MMP-1, -2, and -3 (Gabison, et al. (2005) supra). Evidence that cancer cells overexpress basigin and shed microvesicles containing basigin protein indicates that tumors can modify their local microenvironment by altering the balance between the expression level of MMPs and their physiological inhibitors, the Tissue Inhibitors of Matrix Metalloproteinases (TIMPs) (Sidhu, et al. (2004) Oncogene 23(4):956-963; Caudroy, et al. (2002) Clin. Exp. Metastasis 19(8):697-702). Despite a growing understanding of basigin function in tumor-stromal cell interactions, it has been unclear what protein on the surface of stromal cells functions as the receptor for basigin. Transfection of COS cells with a recombinant form of human basigin demonstrated that basigin can mediate cell adhesion events (Sun & Hemler (2001) Cancer Res. 61(5):2276-2281). Homophilic interactions have been demonstrated for other IGSF proteins including ICAMs (Miller, et al. (1995) J. Exp. Med. 182(5):1231-1241), NCAMs (Zhou, et al. (1993) J. Cell Biol. 122(4):951-960), and cadherins (Tomschy, et al. (1996) EMBO J. 15(14):3507-3514). However, attempts to demonstrate specific homophilic interactions between basigin molecules expressed on separate cells, or between soluble forms of recombinant basigin using surface plasmon resonance have not been successful (Hanna, et al. (2003) supra; Yoshida, et al. (2000) Eur. J. Biochem. 267(14):4372-4380).
Additional functions for basigin have been described. These include the ability of basigin to increase vascular endothelial growth factor (VEGF) production by tumor cells including breast cancer cells (Xiong, et al. (2001) Cancer Research 61:1727-32) as well as host fibroblast cells (Tang, et al. (2005) Cancer Research 65:3198-9). Inhibition of basigin expression inhibits tumor growth in vivo while overexpression of basigin stimulates tumor angiogenesis. Thus, basigin plays an important role in regulating angiogenesis.